PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca2+-permeable AMPA receptors
PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca2+-permeable AMPA receptors
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DOI：
10.1016/j.nbd.2014.05.023
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发表时间：
2014-10-01
影响因子：
6.1
通讯作者：
Moroni, F.
中科院分区：
文献类型：
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作者：
Gerace, E.;Masi, A.;Moroni, F.
聚(ADP-核糖)聚合酶(PARP)的过度激活可能会引发一种类似于神经退行性疾病的神经元死亡。为了研究这一过程，我们将器官型海马片暴露于N-甲基-N‘-硝基-N’-亚硝基胍(MNNG，100IN，5分钟)，这是一种广泛用于激活PARP-1的烷基化试剂。MNNG诱导的CA1区锥体细胞变性形态与短暂的缺氧缺糖(OGD)后相似。MNNG暴露还与PARP-活性的显著增加以及NAD+和ATP含量的显著下降有关。这些效应可以被PARP-1阻止，但不能被PARP-2抑制剂阻止。在我们的实验条件下，细胞死亡不是由AIF易位(甲胎蛋白)或caspase依赖的凋亡过程介导的。此外，我们还发现，PARP激活之后，神经细胞膜的特性显著恶化。在MNNG诱导的细胞死亡中，我们首先利用电生理记录研究了ADP-核糖开放TRPM2通道的能力，但我们得到的结果表明TRPM2通道不参与。然后我们研究了谷氨酸受体-离子通道复合体的参与，我们发现选择性AMPA受体拮抗剂NBQX能有效地防止CA1神经元的丢失，而NMDA拮抗剂MK801则不起作用。此外，我们观察到，MNNG处理增加了GluA1/GluA2 AMPAR亚基的比例，这与CA1区AMPA sEPSCs的IV关系向内纠正有关，而在CA3亚区则没有。因此，1-萘乙酰精胺(NASPM)是缺乏AMPA受体的钙离子通透性GluA2受体的选择性阻断剂，可减少MNNG诱导的CA1锥体细胞死亡。总之，我们的结果表明，核酶PARP-1的激活可能改变AMPA通道的膜蛋白表达和钙通透性，从而影响CA1锥体细胞的功能和生存。(C)2014 Elsevier Inc.保留所有权利。
An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100 IN for 5 min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD+ and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG-induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca2+ permeability of AMPA channels, thus affecting the function and survival of CA1 pyramidal cells. (C) 2014 Elsevier Inc. All rights reserved.